K. Pittman

Randomized Phase III Trial of Temsirolimus Versus Sorafenib As Second-Line Therapy After Sunitinib in Patients With Metastatic Renal Cell Carcinoma

PURPOSE This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. PATIENTS AND METHODS In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non-clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. RESULTS Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. CONCLUSION In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.

Denosumab for the Prevention of Skeletal Complications in Metastatic Castration-Resistant Prostate Cancer: Comparison of Skeletal-Related Events and Symptomatic Skeletal Events

In this analysis of a phase III trial in patients with castration-resistant prostate cancer and bone metastases, treatment with denosumab reduced the risk of skeletal complications vs zoledronic acid regardless of whether the end point was defined as SSE or SRE. Both SSEs and SREs were associated with development of moderate/severe pain among patients with no/mild pain at baseline.

Gemcitabine and carboplatin in carcinoma of unknown primary site: a phase 2 Adelaide Cancer Trials and Education Collaborative study

Cancer of unknown primary site (CUP) represents up to 5% of all cancer diagnoses and is associated with poor survival. We have performed a prospective multicentre phase 2 trial to evaluate efficacy and toxicity of the combination of gemcitabine (G) and carboplatin (C) for patients with CUP. Patients with histologically confirmed metastatic carcinoma in which the primary site of cancer was not evident after prospectively designated investigation and who had ECOG performance status 0–2 were treated with G 1000 mg m−2 intravenously (i.v.) days 1 and 8, and C AUC 5 i.v. on day 8 every 3 weeks to a maximum of nine cycles. The primary end points were response rate, and toxicity, with secondary end points of progression-free survival and overall survival. Fifty-one (23 male, 27 female) patients were enrolled (one patient ineligible), with a median age of 69 years (range 41–83 years). Fifty patients were evaluable for toxicity and 46 patients were evaluable for efficacy. The overall response rate to the GC regimen was 30.5%. With a median follow-up of 24 months, the median progression-free survival was 18 weeks (4.2 months) and the median overall survival was 34 weeks (7.8 months). The frequency of grade 3 or 4 toxicity was low. Nausea/vomiting was the most common side effect, but was usually only mild in severity. Uncomplicated neutropenia (14%), thrombocytopenia (10%) and anaemia (8%) were the most common causes of grade 3–4 toxicity. The regimen was very well tolerated, particularly in the elderly. The GC regimen is an active regimen in CUP with excellent tolerability and should be considered particularly for elderly patients with CUP.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC

Background RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. Patients and methods Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. Results At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1–26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0–29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9–1.6]. Median OS was 22.4 months (95% CI 18.6–33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8–33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9–1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. Conclusions Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. Clinical Trials number ClinicalTrials.gov identifier, NCT00903175

Hyperammonaemic encephalopathy associated with rituximab-containing chemotherapy.

Hyperammonaemic encephalopathy has been infrequently reported after both standard and high‐dose chemotherapy for solid and haematological malignancies. It is important to consider this diagnosis for patients with unexplained behaviour changes or encephalopathy and this case report emphasizes this condition and the importance of early diagnosis and is the first reported in association with rituximab‐containing chemotherapy.

Management and Survival Trends in Advanced Colorectal Cancer

AIMS Significant improvements in the outcome for patients with advanced colorectal cancer (CRC) have been achieved. The median survival for advanced CRC reported in clinical trials now approaches 2 years, but there is often a question as to whether this partly represents patient selection. We aimed to explore whether the availability of new chemotherapy drugs (irinotecan and oxaliplatin) and surgical advances have affected survival in a normal clinical setting. MATERIALS AND METHODS A review of the Queen Elizabeth and Lyell McEwin health service prospective CRC database from 1992 to 2004 was carried out to assess outcome differences between two time cohorts (1 January 1992-31 December 1997 and 1 January 1998-31 December 2004). RESULTS For all patients (n = 744) overall survival was seen to improve over time and is maintained out to 5 years. There have been a number of trends over time (1992-1997 vs 1998-2004) that have probably contributed to this gain; increased overall chemotherapy use (33% vs 43%); use of combination chemotherapy (i.e. oxaliplatin and irinotecan regimens); increased hepatic resection rates (1.9% vs 10.8%) and increased clinical trial uptake (0.6% vs 14.5%). CONCLUSION This current analysis confirms an improvement in survival over time for advanced CRC and this is seen in unselected patients including those over 70 years of age.

A phase I study to determine the safety, tolerability and maximum tolerated dose of green-lipped mussel (Perna canaliculus) lipid extract, in patients with advanced prostate and breast cancer

BACKGROUND This was a phase I trial to determine the maximum tolerated dose (MTD) of a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus), as an inhibitor of 5- and 12-lipo-oxygenase enzymes, in patients with advanced breast and prostate cancers. PATIENTS AND METHODS This was an open-labelled, phase I, dose-escalation study. Proprietary form of green-lipped mussel lipid extract (GLMLE), 260-mg capsule, was administered on a twice-daily schedule, orally. Patients remained on study until disease progression or unacceptable toxicity. RESULTS From December 1999 to May 2003, 17 patients were enrolled. Fifteen of them were male with advanced prostate cancer and two were female with advanced breast cancer. The median age of the patients was 74 years (range 56-85 years). Sixteen patients were assessable for adverse events and dose-limiting toxicity (DLT). Reason for withdrawal from the study included progressive disease (n = 12), death (n = 1) and DLT (n = 3). Two patients had evidence of grade 4 hepatic dysfunction. The MTD was not reached. There were no objective tumour responses noted. CONCLUSIONS GLMLE appears to be a well-tolerated compound in this setting. There appears to be no objective benefit. However, grade 3/4 hepatic toxicity noted in two patients is of concern and should be considered while evaluating patients taking GLMLE or while designing studies with this agent.

Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small-cell lung cancer: an open-label phase II multicentre trial (COVeRT study).

Chemoradiotherapy regimens for stage III non-small-cell lung cancer (NSCLC) require ongoing evaluation. This South Australian multicentre prospective phase II study evaluated the safety, activity and outcomes of combination oral vinorelbine and cisplatin administered concurrently with radiotherapy for stage III NSCLC. Consecutive eligible patients received two cycles of oral vinorelbine 50 mg/m2 day 1 (D1), day 8 (D8) and intravenous cisplatin 50 mg/m2 D1 and D8 in a 21-day cycle. Chemotherapy was administered concurrently with radiotherapy at 60 Gy in 30 fractions, 2 Gy/fraction to the isocentre, all fields treated daily, 5 days a week over 6 weeks using 10 MV photons and three-dimensional conformal radiotherapy. The primary endpoint was to evaluate the progression-free survival (PFS). The secondary end points were safety, response rates and overall survival (OS). Forty-three eligible patients with stage III NSCLC – comprising 21 squamous cell carcinoma, 18 adenocarcinoma and four large cell carcinoma – were studied. Four patients did not complete the treatment. By intention-to-treat analysis, 25% showed a partial response and 65% had stable disease. None achieved a complete response. Of the 39 patients who completed protocol-specified treatment, 11 (28%) showed a partial response and 28 (72%) had stable disease. The median PFS was 25.2 months and the median OS was 48.3 months. Toxicities were manageable and generally mild, with the majority being either grade 1 (n=38) or grade 2 (n=21). Toxicities were mainly of oesophagitis, pneumonitis, fatigue, nausea and dysphagia. Two cycles of chemotherapy with oral vinorelbine and cisplatin administered concurrently with radical radiation had an acceptable toxicity profile and was active in inoperable stage III NSCLC. PFS and OS outcomes were encouraging. This regimen warrants further investigation.

Reversing Hyperammonemia in Neuroendocrine Tumors.

Ammonia is a neurotoxin that is normally cleared by the intact liver and if not, hyperammonemia results in hepatic encephalopathy. Hyperammonemia may be owing to primary or secondary causes. Early diagnosis is important to prevent permanent brain damage. Advanced malignancy involving the liver is associated with hyperammonemia as a result of abnormality of the portal venous system or massive hepatic tumor burdon. Neuroendocrine tumors are an example of a malignant process that frequently involves the liver but despite this, may still have a relatively good prognosis, and are often characterized by chronic manageable symptoms and slow progression. Hyperammonemia in neuroendocrine tumor would represent a potentially reversible but ongoing process associated with an indolent malignancy. We present 2 cases that are examples of this diagnosis and discuss the diagnostic and management issues that may arise.

Small cell lung cancer: patterns of care and their influence on survival - 25 years experience of a single Australian oncology unit.

Aim:  Evidence supporting improved outcomes for small cell lung cancer (SCLC) in recent decades is limited. This study aimed to identify patterns of care and survival over two time periods; 1 January 1987 to 31 December 1996 (cohort A) and 1 January 1997 to 31 December 2006 9 (cohort B).